Developing tissues rely on the integration of several biochemical pathways to regulate neural differentiation. Both EGF-Receptor and Notch signaling are essential to this process, and modulating the balance between these pathways is critical in limiting the number of cells that differentiate as neurons. In the developing vertebrate eye, the first cell type to form is the retinal ganglion cell (RGC); RGCs are essential for transducing and relaying visual information to the brain. Differentiation of RGCs requires expression of the transcription factor Ath5, and the number of RGCs that form is limited by activity of the Notch signal transduction pathway. Similarly, in the developing Drosophila eye, differentiation of the first cell type, the R8 photoreceptor, requires expression of the Ath5 homolog Atonal; this expression is also limited by Notch activity. This proposal seeks to elucidate the activities of two Ig-superfamily cell adhesion molecules that modulate Notch and EGF-Receptor signaling during Drosophila eye development. Echinoid (ed) and Friend of Echinoid (fred) are homologous transmembrane proteins; mutations in these genes disrupt expression of Atonal and normal patterning of R8 photo receptors. Through a variety of genetic, molecular, and biochemical approaches, Dr. Spencer proposes to examine the roles of Ed and Fred in retinal development, characterize the functions of their intracellular and extracellular domains, and identify the proteins with which they associate directly. These experiments will further our understanding of the roles of cell adhesion molecules in modulating signaling pathways, and of the cues that drive retinal differentiation. The similarity between the pathways that regulate differentiation of RGCs in vertebrates and R8s in Drosophila suggests that this work will in time also broaden our understanding of the genes that regulate RGC formation. [unreadable] [unreadable] [unreadable]